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ADRIA’s MYCOBUTIN SHIPMENTS WILL BEGIN MID-JANUARY; FIRST PREVENTATIVE FOR AIDS-RELATED MYCOBACTERIUM AVIUM COMPLEX WILL COST $2,000/YEAR AT MINIMUM

Executive Summary

Adria will begin shipping Mycobutin in mid-January, three weeks following FDA's Dec. 23 approval of the macrolide antibiotic as the first agent for prophylaxis of Mycobacterium avium complex in AIDS patients. Mycobutin received a "1P" rating designating a new molecular entity given a priority review. Mycobutin has been available under a Treatment IND since March. Over 2,000 patients have received the drug in the program. In a Dec. 23 "Talk Paper" on the approval, FDA estimated that 30%- 50% of patients with advanced HIV infection develop MAC. Adria's price to wholesalers for Mycobutin is $2.73 per 150 mg capsule. The recommended dose for MAC prophylaxis is 300 mg per day, putting the cost of therapy at a minimum of $2,000 per year. Adria will offer a patient assistance program similar to those of other AIDS-related therapies. Mycobutin (NDA 50-689) is indicated for "the prevention of disseminated Mycobacterium avium disease in patients with advanced HIV infection." In the 1,146-patient clinical trial database, "participants who received Mycobutin were one-third to one-half as likely to develop MAC bacteremia as were participants who received placebo," labeling notes. In one trial the one-year cumulative incidence of MAC bacteremia was 9% for patients taking Mycobutin and 22% for patients randomized to placebo. In the other trial, the percentage of patients developing MAC bacteremia was 13% for Mycobutin compared to 28% for placebo. Patients also showed "a corresponding reduction in the following signs and symptoms of disseminated MAC disease: fever, night sweats, weight loss, fatigue, abdominal pain, anemia and hepatic dysfunction." Labeling does not specify a CD4 cell count at which to begin therapy, describing only the entry criteria for the two pivotal trials, which were CD4 counts of less than 200 in one trial and a median CD4 count of 40 in the other. "Most cases of MAC bacteremia (approximately 90% in these studies) occurred among participants whose CD4 count at study entry was [less than] 100 cells/microliter," labeling notes. The issue of when to initiate therapy was discussed at a September meeting of the Antiviral Drug Products Advisory Committee ("The Pink Sheet" Sept. 28, p. 3). While some committee members felt that only patients with CD4 counts of less than 100 should receive Mycobutin, the committee ultimately recommended against setting a limit on the CD4 counts and left the wording of the indication to FDA. The advisory committee considered the Mycobutin NDA twice, in June and in September, before recommending the drug for approval. At the first meeting, the committee struggled for 12 hours to conclude that the information submitted was inadequate and would require further analyses. While Adria only began to file the NDA in January 1992 and submitted additional data as late as May, FDA decided to rush the incomplete application to the committee for consideration because it wanted input on the design and implementation of future drug trials in MAC infection. Mycobutin labeling warns against use of the product in patients with active tuberculosis and cautions that the drug may reduce the activity of other drugs that are also affected by rifampin. "Administration of single-agent Mycobutin to patients with active tuberculosis is likely to lead to the development of tuberculosis that is resistant both to Mycobutin and rifampin," labeling notes. "Tuberculosis in HIV-positive patients is common and may present with atypical or extrapulmonary findings," labeling adds. Because rifabutin is structurally similar to rifampin, and the latter drug is known to reduce the activity of a number of drugs, labeling states that Mycobutin "may be expected to have some effect on these drugs as well." The drugs with which rifampin has been shown to interact include dapsone, narcotics, anticoagulants, corticosteroids, cyclosporine, oral contraceptives, oral hypoglycemics, analgesics and a number of other drugs. Unlike rifampin, however, rifabutin "appears not to affect the acetylation of isoniazid," which is used to prevent and treat tuberculosis, labeling notes. Since Mycobutin "may be associated with neutropenia, and more rarely thrombocytopenia, physicians should consider obtaining hematologic studies periodically," labeling notes. The label also states that physicians should advise patients that "urine, feces, sputum, perspiration, tears and skin may be colored brown-range with rifabutin and some of its metabolites" and that "soft contact lenses may be permanently stained." The most frequent adverse events reported with Mycobutin were discolored urine in 30% of patients and an 11% incidence of rash and gastrointestinal symptoms in 23% of patients. Twice as many patients were discontinued from Mycobutin therapy than placebo- treated patients in the controlled clinical trials: the primary reasons for discontinuation of Mycobutin were rash (4%), GI intolerance (3%) and neutropenia (2%). Due to the agency's concern about drug interactions, FDA has suggested that Adria conduct postmarketing studies to determine whether Mycobutin has an effect on the activity of oral contraceptives, dapsone and probenecid. The agency also requested that the company perform pharmacokinetic studies of Mycobutin in women and children. Adria has ongoing studies with Mycobutin in combination with clarithromycin, azithromycin and other antibacterials in the treatment of patients with active MAC infection. The drug will be manufactured by Farmitalia Carlo Erba, a subsidiary of Adria parent Ferruzzi-Montedison.
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